Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

Abstract

Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBVrelated HCC is the male predominance, with a male to female ratio of 5-7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.androgen-responsive element H epatocellular carcinoma (HCC) is one of the leading cancers in the world, with more than half a million deaths per year (1). Chronic hepatitis, caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, is a major risk factor for the development of HCC (2). Another risk factor is the male gender. HCC occurs much more frequently in men than in women, with a male to female ratio ranging from 2:1 to 11:1 (3). Both animal and human studies support the importance of androgen signaling in determining the male preference of HCC (4-13). It was also noted that the expression and activation of androgen receptor (AR) is increased in the tumor tissues as well as in the surrounding nontumorous liver tissue of patients with HCC (14-16). Intriguingly, the gender preference of HCC differs between HBV-and HCV-related cases. The male predominance in HBV-related HCC is significantly higher than that of HCVrelated HCC, with a ratio of 5-7:1 vs. 2-3:1 (17, 18). Among male HBV carriers, those with a higher level of serum androgen and more active AR gene alleles have a significantly increased risk of HCC (19,20). However, these two factors have not been reported to contribute to the increased risk of HCV-related HCC. Thus, HBV infection might uniquely cooperate with androgen signaling to accelerate hepatocarcinogenesis, raising the possibility that certain HBV gene(s) could modulate AR signaling activity and HCC development.AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily (21,22). It consists of several functional domains individually responsible for the activities ...

Androgen receptor in hepatocarcinogenesis: Recent developments and perspectives

“…These results are in agreement with the finding that AR and miR-216a were concordantly overexpressed in clinical specimens, while an inverse correlation between TSLC1 and miR-216a was also identified in these liver tissues (25). The presence of the hepatitis B virus (HBV) X protein (HBx) can further augment the effect of AR-mediated miR-216a transcription, due to its known ability to enhance AR activity (38,39). Notably, recent studies have indicated that miRNAs, including miR-224, miR-221, miR-122a and miR-223, demonstrate deregulated expression patterns in male HCC patients (25).…”

Identification of androgen response elements in the enhancer I of hepatitis B virus: A mechanism for sex disparity in chronic hepatitis B #

“…7 Our previous study showed that HBx could enhance the transcriptional activity of AR, which leads to an increased risk of HCC. 8 The current study further disclosed a new role of AR in liver carcinogenesis, namely the activation of HBV transcription and replication. A positive regulatory loop might exist between the increase in AR transcription activities by HBx, and the increase in HBV (HBx) gene expressions through the ligand-stimulated AR pathway (summarized in Fig.…”

“…Consistent with this, we recently showed that HBV X protein (HBx) can enhance the transcriptional activity of AR in a ligand concentration-dependent manner, which may explain the male predominance of HBV-related HCC. 8 Because of the …”

Androgen Receptor and Hepatocellular Carcinoma

“…HBx, which has a size of ~17 kDa, can physically bind to AR [49]. HBx-mediated enhancement of AR activity is androgen-dependent and could be mediated through indirect mechanism involving calcium and c-Src signaling pathways [50]. HBx enhances the AR transcriptional activity through two kinases: c-Src and glycogen synthase kinase-3beta kinase [51].…”